Assessment of GS-9219 in a pet dog model of non-Hodgkin's lymphoma.

PURPOSE: To assess, in dogs with naturally occurring non-Hodgkin's lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies. EXPERIMENTAL DESIGN: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkin's lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment. RESULTS: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkin's lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkin's lymphoma. High 3'-deoxy-3'-(18)F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016). CONCLUSIONS: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkin's lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.

Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs.

BACKGROUND: Hemangiosarcoma (HSA) is a highly metastatic and often rapidly fatal tumor in dogs. At present, conventional adjuvant chemotherapy provides only a modest survival benefit for treated dogs. Continuous oral administration of low-dose chemotherapy (LDC) has been suggested as an alternative to conventional chemotherapy protocols. Therefore, we evaluated the safety and effectiveness of LDC using a combination of cyclophosphamide, etoposide, and piroxicam as adjuvant therapy for dogs with stage II HSA. HYPOTHESIS: We hypothesized that oral adjuvant therapy with LDC could be safely administered to dogs with HSA and that survival times would be comparable to those attained with conventional doxorubicin (DOX) chemotherapy. ANIMALS: Nine dogs with stage II splenic HSA were enrolled in the LDC study. Treatment outcomes were also evaluated retrospectively for 24 dogs with stage II splenic HSA treated with DOX chemotherapy. METHODS: Nine dogs with stage II splenic HSA were treated with LDC over a 6-month period. Adverse effects and treatment outcomes were determined. The pharmacokinetics of orally administered etoposide were determined in 3 dogs. Overall survival times and disease-free intervals were compared between the 9 LDC-treated dogs and 24 DOX-treated dogs. RESULTS: Dogs treated with LDC did not develop severe adverse effects, and long-term treatment over 6 months was well-tolerated. Oral administration of etoposide resulted in detectable plasma concentrations that peaked between 30 and 60 minutes after dosing. Both the median overall survival time and the median disease-free interval in dogs treated with LDC were 178 days. By comparison, the overall survival time and disease-free interval in dogs treated with DOX were 133 and 126 days, respectively. CONCLUSIONS: Continuous orally administered LDC may be an effective alternative to conventional high-dose chemotherapy for adjuvant therapy of dogs with HSA.

Diagnosis of mediastinal masses in dogs by flow cytometry.

BACKGROUND: Biopsy of mediastinal masses can be invasive, but the procedure may be necessary if cytology of a mass aspirate is inconclusive. The 2 most common mediastinal masses, lymphoma and thymoma, may both be comprised of small lymphocytes. We investigated the ability of flow cytometry to distinguish between these 2 neoplasms. HYPOTHESIS: Flow cytometry of mediastinal mass aspirates may provide a definitive diagnosis of thymoma or lymphoma, reducing the need for biopsy. ANIMALS: Dogs with mediastinal masses presenting to the Veterinary Teaching Hospital/Animal Cancer Center were included in the study. METHODS: Aspirates obtained over 2 years that met the inclusion criteria (i.e. sufficient viable cells and a definitive diagnosis by means other than flow cytometry) were analyzed by flow cytometry to determine the percentage of cells expressing B- and T-cell markers, and co-expressing CD4 and CD8. RESULTS: All cases of thymoma (n = 6) consisted of > or = 10% lymphocytes coexpressing CD4 and CD8, a phenotype that is characteristic of thymocytes, whereas 6 of 7 lymphomas contained <2% CD4+CD8+ lymphocytes. The CD4+CD8+ lymphoma could be readily distinguished flow cytometrically from thymoma by light scatter properties. The phenotypes of the remaining lymphomas were CD4+ T cell (4), CD34+ (1) and B cell (1). CONCLUSIONS: Our studies demonstrate that flow cytometry is a useful tool for discriminating mediastinal masses. Lymphocyte-rich mediastinal masses could be unambiguously identified by flow cytometry in 13/13 cases.